Naoe Akimoto

A novel treatment for bile duct injury with a tissue-engineered bioabsorbable polymer patch

BACKGROUND With the recent widespread use of laparoscopic cholecystectomy and living-donor liver transplantation, complications involving the biliary system, and stenosis in particular, are encountered frequently. Although various invasive and noninvasive techniques are now available for the treatment of biliary stenosis, recurrence and other problems limit their value and utility. Our group sought to investigate whether a bioabsorbable polymer (BAP) patch could serve as a novel treatment for biliary stenosis. METHODS In anesthetized hybrid pigs (n = 12), a spindle-shaped portion of the lower common bile duct wall was excised, and a BAP patch was implanted at the excision site. The animals underwent repeat laparotomy at 5 weeks (n = 6) and at 4 months (n = 6) after implantation to recover the graft sites for gross and histologic studies. Blood chemistry was analyzed from samples taken during the patch implantation and recovery. RESULTS All of the recipient pigs survived until killing. All gained weight and showed no evidence of jaundice. The BAP-patched duct remained patent without obstruction at 5 weeks postimplantation. Blood chemistry did not reveal any increases in hepatobiliary enzyme activities. Histology showed accessory glandular structures in the neo-bile duct. At 4 months, the graft site was indistinguishable from the native duct. Intra-operative cholangiography revealed dilation of the patched site, but no dilatation of the intrahepatic bile ducts. Blood chemistry values were within normal ranges. Histology at the site of the patch confirmed the growth of a cuboidal columnar epithelium similar to that of the native duct. CONCLUSION The bile duct was dilated only focally at the site of implantation. This newly designed substitute has potential for application as a novel treatment for biliary injury and stenosis.

Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model

BackgroundStricture formation is one of the major complications after endoscopic removal of large superficial squamous cell neoplasms of the esophagus, and local steroid injections have been adopted to prevent it. However, fundamental pathological alterations related to them have not been well analyzed so far. The aim of this study was to analyze the time course of the healing process of esophageal large mucosal defects resulting in stricture formation and its modification by local steroid injection, using an animal model.MethodsEsophageal circumferential mucosal defects were created by endoscopic mucosal dissection (ESD) for four pigs. One pig was sacrificed five minutes after the ESD, and other two pigs were followed-up on endoscopy and sacrificed at the time of one week and three weeks after the ESD, respectively. The remaining one pig was followed-up on endoscopy with five times of local steroid injection and sacrificed at the time of eight weeks after the ESD. The esophageal tissues of all pigs were subjected to pathological analyses.ResultsFor the pigs without steroid injection, the esophageal stricture was completed around three weeks after the ESD on both endoscopy and esophagography. Histopathological examination of the esophageal tissues revealed that spindle-shaped α-smooth muscle actin (SMA)-positive myofibroblasts arranged in a parallel fashion and extending horizontally were identified at the ulcer bed one week after the ESD, and increased contributing to formation of the stenotic luminal ridge covered with the regenerated epithelium three weeks after the ESD. The proper muscle layer of the stricture site was thinned with some myocytes which seemingly showed transition to the myofibroblast layer. By contrast, for the pig with steroid injection, esophageal stricture formation was not evident with limited appearance of the spindle-shaped myofibroblasts, instead, appearance of stellate or polygocal SMA-positive stromal cells arranged haphazardly in the persistent granulation tissue of the ulcer site.ConclusionsProliferation of spindle-shaped myofibroblasts arranged in a parallel fashion is likely to play an important role in stricture formation after circumferential mucosal defects by esophageal ESD, which may be related to the thinning of the proper muscle layer in the healing course of the defects. Local steroid injection seems to be effective to prevent the stricture through the modification of this process.

Experimental trial for perforation caused by esophageal endoscopic submucosal dissection using a biodegradable polymer stent in an animal model

Our group has developed a biodegradable covered stent (BDCS) composed of bioabsorbable polymer for the repair of emergent esophageal perforation. The BDCS is composed of a 50:50 copolymer of polylactic acid and polycaprolactone reinforced with polyglycolic acid fibers (Fig. 1a). This study was conducted at the animal facility in Saitama Medical University International Medical Center, Saitama, Japan, after the approval of the Animal Care and Use Committee. Under general anesthesia, a mucosal defect with a major axis of approximately 15 mm was prepared in the middle esophagus by endoscopic submucosal dissection (ESD) in four pigs. Then, ESD was carried out with a Flash knife (KD-2618 JN-15; Fujinon Corp., Saitama, Japan) at a length of 1.5 mm. An approximately 5-mm perforation was also prepared in the defective mucosal region (Fig. 1b). Perforation was confirmed by observing tissue moving with respiratory variation paradoxically against the submucosal layer. The BDCS was inserted inside the esophagus endoscopically to cover the opening (Fig. 1c).The animals started taking fluid at 1 day after the procedure and started feeding on a normal diet at 5 days. The animals that received the BDCS survived until killing without any complications. The stent was still observed at 1 week after the implantation (Fig. 2a) but was wholly undetectable by 2 weeks (Fig. 2b). There was no stenosis or any kind of infection around therepaired wall (Fig. 2c). Normal mucosa similar to that of the native wall was confirmed histologically (Fig. 2c). In the future, the BDCS should be applied in humans through further case accumulation/review. However, this procedure may become a useful strategy for treating esophageal wall injury, which may otherwise lead to a fatal outcome, including esophageal ESD-related perforation.

A Newly Designed Anal Fistula Plug: Clinicopathological Study in an Experimental Iatrogenic Fistula Model

We report on a clinicopathologic study in an animal model of treatment with a new bioabsorbable polymer plug (BAPP). Over a 2-week period, 6 porcine models, which each had 4 anal fistulae, were created using Blake drains. The pigs were divided into 2 groups: the BAPP-treatment group (n = 12 fistulae) and the control group (n = 12 fistulae). Two weeks later, the pigs were humanely killed, and the perianal sites were excised and examined with gross and pathologic studies. Each fistula in the BAPP group was completely cured. In the pathologic study, the treatment sites had little disarray, few defects in the muscular layer, and small numbers of inflammatory cells. The control group had a significantly greater number of inflammatory cells and microabscesses than the BAPP group. The newly developed BAPP reduced the infection and induced good healing in anal fistulae. The BAPP may be a useful new device for the clinical treatment of anal fistulae.

Novel pancreatoenteric reconstruction using a bioabsorbable polymer sheet and biocompatible bond

BACKGROUND Pancreatoenteric reconstruction often induces severe complications. Although many techniques have been developed to prevent these complications, no standard technique has yet emerged. We developed a novel technique, sutureless pancreatoenteric anastomosis, that uses a bioabsorbable polymer sheet (BAPS) and biocompatible bond (BCB) to prevent the complications associated with pancreatoenteric anastomosis. We used large animals to investigate whether this technique is suitable for clinical use. MATERIALS AND METHODS Six pigs were laparotomized under general anesthesia. The body of the pancreas was divided, and the proximal stump was closed by suture. A BAPS coated with BCB was rolled and fixed around the distal pancreatic stump to form a cylinder that was anastomosed to the duodenum without suturing the pancreas. Twenty weeks after the initial operation the operated sites were extirpated and evaluated grossly and histologically. RESULTS All operated pigs survived without pancreatic juice leakage until they were killed. At 20 wk, the BAPS could not be identified. The pancreatic stump was tightly affixed to the duodenum. Histologic study revealed that the pancreatic stump and duodenal wall were continuous and the main pancreatic duct opened into the lumen of the duodenum. CONCLUSIONS Sutureless pancreatoenterostomy with BAPS and BCB may be clinically feasible.